POS0222 POLYARTICULAR ARTHRITIS AND ADULT-ONSET OSTEOLYSIS CAUSED BY MUTATIONS IN THE ASAH1 GENE: FARBER DISEASE CLINICAL PRESENTATIONS IN THE CONTEXT OF A FIRST-EVER NATURAL HISTORY STUDY
Authors: L. Seefried, K. Crosby, A. Solyom
Journal: Annals of the Rheumatic Diseases (2022)

Background Farber disease is frequently misdiagnosed as polyarticular juvenile idiopathic arthritis or seronegative rheumatoid arthritis which leads to a delay in diagnosis for many patients. Farber disease is an ultra-rare lysosomal storage disease caused by mutations in the ASAH1 gene. The resulting deficiency of the acid ceramidase enzyme leads to accumulation of the pro-inflammatory and pro-apoptotic sphingolipid ceramide. Accumulation of ceramide throughout the body leads to the symptoms of Farber disease. Cardinal symptoms include joint disease (polyarticular arthritis and contractures), subcutaneous nodules, and a hoarse or weak voice due to laryngeal nodules. The phenotypic spectrum of Farber disease ranges from rapidly progressive disease causing death in infancy to moderate or slowly progressive disease with survival into late adulthood. Symptoms may vary in severity across patients and phenotypes. Objectives To further define the symptoms of Farber disease, including joint disease, subcutaneous nodules, dysphonia, and osteolysis, which can lead to referral to rheumatology or related specialties. To understand the clinical presentation and broad phenotypic spectrum of this rare disease to aid in clinical diagnosis and reduce diagnostic delay. Methods The Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease ( NCT03233841 ) was the first systematic clinical study of the natural history of Farber disease. The study collected retrospective and prospective data on living and deceased patients, including demographics, clinical presentation, phenotype, diagnostic history, and patient reported outcomes. Results 45 patients with Farber disease (27 living, 18 deceased) who had or had not undergone hematopoietic stem cell transplant (HSCT) were enrolled from 16 centers in 9 countries. A cohort of 24 living non-HSCT patients were followed prospectively. The patients represented the broad phenotypic spectrum of Farber disease, from rapidly progressive (severe) to slowly progressive (attenuated). In patients whose data was available for analysis, the average age of patients at enrollment was 7.2 years (range 1 to 28 years). The average age of onset of joint disease (arthritis and/or contractures) was 15 months (range 3 months to 7 years), of subcutaneous nodules was 13 months (range 3 months to 5 years), and of dysphonia was 13 months (range birth to 8 years). The average time from onset of symptoms to Farber disease diagnosis was 2 years (range &lt;1 to 12 years). At baseline, the mean number of joints affected with active arthritis was 11.3 (range 0-36) and the mean number affected with contractures was 18 (range 0-38). 12.5% of patients were reported to have a bone disorder such as osteoporosis or osteolysis. The Child Health Assessment Questionnaire Disability Index (CHAQ) ranging from 0 (no impairment) to 3 (unable to do) was high, with mean scores of 2.62-3.00 across visits. Conclusion Data from the Farber disease natural history study further defined the cardinal symptoms, phenotypic spectrum, and high disease-related burden in patients with Farber disease. The large number of joints affected with arthritis or contractures reflects that patients with Farber disease are often referred to rheumatology and can be misdiagnosed with polyarticular juvenile idiopathic arthritis or seronegative rheumatoid arthritis. Demographic information and numbers of patients enrolled indicate that Farber disease is likely not as rare as previously thought. ASAH1 genetic testing for adult and pediatric patients referred to the rheumatology clinic with symptoms including polyarticular arthritis, subcutaneous nodules, dysphonia, or osteolysis, may shorten the time to diagnosis in patients with Farber disease. Disclosure of Interests Lothar Seefried Speakers bureau: Aceragen, Amgen, Alexion, Biomarin, Chiesi, KyowaKirin, Novartis, Theramex, and UCB, Consultant of: Amgen, Alexion, Biomarin, Chiesi, KyowaKirin, Novartis, Theramex, and UCB, Grant/research support from: Alexion, KyowaKirin and Novartis, Kathleen Crosby Employee of: Aceragen, Alexander Solyom Employee of: Aceragen